title: Discovery and structure-activity relationship of 3-aminopyrid-2-ones as potent and selective interleukin-2 inducible T-cell kinase (Itk) inhibitors.
abstract: Interleukin-2 inducible T-cell kinase (Itk) plays a role in T-cell functions, and its inhibition potentially represents an attractive intervention point to treat autoimmune and allergic diseases. Herein we describe the discovery of a series of potent and selective novel inhibitors of Itk. These inhibitors were identified by structure-based design, starting from a fragment generated de novo, the 3-aminopyrid-2-one motif. Functionalization of the 3-amino group enabled rapid enhancement of the inhibitory activity against Itk, while introduction of a substituted heteroaromatic ring in position 5 of the pyridone fragment was key to achieving optimal selectivity over related kinases. A careful analysis of the hydration patterns in the kinase active site was necessary to fully explain the observed selectivity profile. The best molecule prepared in this optimization campaign, 7v, inhibits Itk with a K(i) of 7 nM and has a good selectivity profile across kinases.
authors.affiliation: Department of Chemistry, Vertex Pharmaceuticals (Europe) Ltd., 88 Milton Park, Abingdon, Oxfordshire OX14 4RY, UK. jean-damien_charrier@vrtx.com
authors.forename: Jean-Damien
authors.initials: JD
authors.lastname: Charrier
authors.forename: Andrew
authors.initials: A
authors.lastname: Miller
authors.forename: David P
authors.initials: DP
authors.lastname: Kay
authors.forename: Guy
authors.initials: G
authors.lastname: Brenchley
authors.forename: Heather C
authors.initials: HC
authors.lastname: Twin
authors.forename: Philip N
authors.initials: PN
authors.lastname: Collier
authors.forename: Sharn
authors.initials: S
authors.lastname: Ramaya
authors.forename: Shazia B
authors.initials: SB
authors.lastname: Keily
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Durrant
authors.forename: Ronald M A
authors.initials: RM
authors.lastname: Knegtel
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Tanner
authors.forename: Kieron
authors.initials: K
authors.lastname: Brown
authors.forename: Adam P
authors.initials: AP
authors.lastname: Curnock
authors.forename: Juan-Miguel
authors.initials: JM
authors.lastname: Jimenez
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D020134:Catalytic Domain; D015195:Drug Design; D006860:Hydrogen Bonding; D008301:Maleimides / Q000737:chemistry; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D008301:Maleimides; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase